* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Cancer Prone Disease Section Waardenburg syndrome (WS) Atlas of Genetics and Cytogenetics
Primary transcript wikipedia , lookup
Genomic imprinting wikipedia , lookup
Public health genomics wikipedia , lookup
Long non-coding RNA wikipedia , lookup
Epigenetics of diabetes Type 2 wikipedia , lookup
Epigenetics of human development wikipedia , lookup
Genome (book) wikipedia , lookup
Designer baby wikipedia , lookup
Saethre–Chotzen syndrome wikipedia , lookup
Frameshift mutation wikipedia , lookup
Gene expression profiling wikipedia , lookup
Gene expression programming wikipedia , lookup
Artificial gene synthesis wikipedia , lookup
History of genetic engineering wikipedia , lookup
Gene therapy of the human retina wikipedia , lookup
Neuronal ceroid lipofuscinosis wikipedia , lookup
Microevolution wikipedia , lookup
Oncogenomics wikipedia , lookup
Epigenetics in learning and memory wikipedia , lookup
Site-specific recombinase technology wikipedia , lookup
Therapeutic gene modulation wikipedia , lookup
Nutriepigenomics wikipedia , lookup
Mir-92 microRNA precursor family wikipedia , lookup
Epigenetics of neurodegenerative diseases wikipedia , lookup
Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Cancer Prone Disease Section Review Waardenburg syndrome (WS) Carolina Vicente-Dueñas, Camino Bermejo-Rodríguez, María Pérez-Caro, Inés GonzálezHerrero, Manuel Sánchez-Martín, Isidro Sánchez-García Laboratorio 13, Instituto de Biologia Molecular y Celular del Cancer (IBMCC), Centro de Investigacion del Cancer, Campus Unamuno, 37.007-Salamanca, Spain (CVD, CBR, MPC, IGH, MSM, ISG) Published in Atlas Database: February 2005 Online updated version: http://AtlasGeneticsOncology.org/Kprones/WaardenburgID10089.html DOI: 10.4267/2042/38200 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2005 Atlas of Genetics and Cytogenetics in Oncology and Haematology canthorum (lateral displacement of the inner canthi); WS2 has no other symptoms; WS3 is associated with upper limb deformity; and WS4, with megacolon. Identity Alias Klein-Waardenburg syndrome (WS3) Waardenburg syndrome with upper limb anomalies (WS3) White forelock with malformations (WS3) Waardenburg-Hirschsprung disease (WS4) Waardenburg syndrome variant (WS4) Shan-Waardenburg syndrome (WS4) Hirschsprung disease with pigmentary anomaly (WS4) Note Waardenburg syndrome (WS) is an auditorypigmentary syndrome caused by a deficiency of melanocytes and other neural crest-derived cells. The disease was named for Petrus Johannes Waardenburg, a Dutch ophthalmologist (1886-1979) who was the first to notice that people with two different coloured eyes frequently had hearing problems. Inheritance Inherited in an autosomal dominant manner with an incidence of 1 in 40 000 newborns. Almost 90% of patients have an affected parent but the symptoms in the parent can be quite different from those in the child. Phenotype and clinics Disease with variable penetrance and several know clinical types. Characteristics may include depigmentation of the hair and skin, congenital deafness, heterochromia iridis, medial eyebrow hyperplasia, hypertrophy of the nasal root, and especially dystopia canthorum. The underlying cause may be defective development of the neural crest (neurocristopathy). Waardenburg's syndrome may be closely related to piebaldism. Klein-Waardenburg syndrome refers to a disorder that also includes upper limb abnormalities. Neoplastic risk Slight increased risk for rhabdomyosarcoma. Treatment No specific treatment is available for Waardenburg syndrome. Attention must be paid to any hearing deficit and hearing aids and appropriate schooling may need to be provided. Type 4 patients with constipation require special attention to their diet and medications to keep their bowels moving. Prognosis Clinics With correction of hearing deficits, affected people should be able to lead a normal life. Note Waardenburg syndrome (WS) is a hereditary auditorypigmentary syndrome, the major symptoms being congenital sensorineural hearing loss and pigmentary disturbance of eyes, hair and skin. Depending in additional symptoms, WS can be classified into four types: WS type I (WS1) is associated with facial deformity such as dystopia Atlas Genet Cytogenet Oncol Haematol. 2005; 9(2) Genes involved and proteins Note WS can be classified into for types. At least one gene responsible for each type of WS has been cloned and for these cloning procedures mice with pigmentation 181 Waardenburg syndrome (WS) Vicente-Dueñas C et al. anomalies have contributed greatly. Six genes contributing to this syndrome- PAX3, SOX10, MITF, SLUG, EDN3 and EDNRB- have been cloned so far, all of them necessary for normal development of melanocytes. SOX10 Location 22q13 DNA/RNA Description: 5 exons. PAX3 Protein Location 2q35-q37 Note PAX3 is an important gene in muscle development and muscle-producing neoplasms such as rhabdomyosarcomas. DNA/RNA Description: 10 exons. Protein Description: 206-215 residues. Expression: is expressed during embryonic development. Skeletal muscle, esophagus, cerebellum, pancreas, liver and stomach. Function: Transcription factor. Mutations Mutations in PAX3, which encodes a paired homeodomain transcription factor, are responsible for Waardenburg syndrome 1 and 3. PAX3 was shown to bind and transactivate the MITF promoter, thereby demonstrating the role of PAX3 in the regulation of MITF expression. This observation supports an epistatic relationship between MITF and PAX3 and can explain the pigmentary disorders observed in WS1 and 3, because MITF controls melanocyte development. PAX3 defects affect neural crest cell derivatives, resulting in the presence of craneofacial malformations. SOX10, a protein that modulates other transcription factors (including PAX3) belongs to the high mobility group (HMG) box superfamily of DNA-binding proteins. It is first expressed during development in cells of the neural crest that contributes to the forming peripheral nervous system, and can be detected in the sensory, sympathetic and enteric ganglia and along nerves. SOX10 is also transiently expressed in melanoblast. Description: 466 residues. Expression: During development in cells of the neural crest. Function: Transcription factor. Mutations Mutations in Sox10 also result in WS4. How mutations in this gene lead to deafness and pigmentary abnormalities, shared by all the WS subtypes, was not elucidated. It was tempting to propose that the WS4 genes are directly or indirectly involved in the regulation of MITF expression that is crucial for melanocyte development. SOX10 binds and transactivates the MITF promoter, whereas Sox10 mutants found in WS4 patients failed to stimulate the MITF promoter. Thus, there is an epistatic relationship between SOX1 and MITF, thereby giving a molecular basis for the audio-pigmentary defect in patients with WS4. SOX10 joins Pax3, CREB and LEF1 in the list of transcription factors that control MITF expression. GENE Syndrome Specific symptoms PAX3 WS1; WS3 Dysthopia canthorum, hypoplasia of limb muscle; contracture of elbows, fingers. MITF WS2 Main symptoms only (auditory-pigmentary syndrome) SLUG WS2 Main symptoms only (auditory-pigmentary syndrome) EDNRB WS4 Hirschsprung’s disease EDN3 WS4 Hirschsprung’s disease SOX10 WS4 Hirschsprung’s disease Table 1: Genes involved in Waardenburg syndrome (WS). Atlas Genet Cytogenet Oncol Haematol. 2005; 9(2) 182 Waardenburg syndrome (WS) Vicente-Dueñas C, et al. MITF Mutations Mice lacking Slugh have patchy deficiency of melanocytes, a phenotype similar to human Waardenburg syndrome. It has been shown that some human patients with Waardenburg syndrome carry homozygous deletions of SLUG as their only detected genetic abnormality, thus defining a recesive form of type 2 WS. Preliminary investigations of the role of SLUG in melanocyte development show that it is a downstream target of MITF, which acts on an E-box sequence in the SLUG promoter. Location 3p14.1-p12.3 DNA/RNA Description: 9 exons. Protein Microphtalmia-associated transcription factor (MITF) is a basic helix-loop-helix, leucin zipper transcription factor that plays a pivotal role in survival and differentiation of melanocytes, the cells that produce melanin pigments. MITF has been demonstrated to upregulate the expression of the genes involved in melanin synthesis, such as tyrosine, TRP1, and TRP2. Further MITF is thought to be a master gene in melanocyte differentiation, because its forced expression in fibroblast leads to the expression of melanocytes-specific enzymes required for melanin synthesis. Description: 520 residues. Expression: in melanocytes. Function: Transcription factor. Mutations In humans, mutations, of MITF are responsible for Waardenburg syndrome (WS) type 2, characterized by pigmentation abnormalities and sensorineural deafness due to the absence of melanocytes from the stria vascularis of the inner ear. In mice, mutations in the microphthalmia gene cause pigmentation disorders because of the absence of melanocytes, supporting the involvement of MITF in melanocyte survival. Over 20 different Mitf mutations have been described in mice. They all result in a deficiency in skin or coat melanocytes ranging in severity from minor pigmentary defects with normal eyes to total lack of coat and eye pigmentation, small colobomatous eyes, deafness and in some instances osteopetrosis. EDN3 (ENDOTHELIN 3) Location 20q13.2-q13.3 DNA/RNA Description: 5 exons. Protein Description: 230 residues. Expression: Trophoblasts, placental stem villi vessels. Function: Peptide hormone. EDNRB (ENDOTHELIN RECEPTOR, TYPE B) Location 13q22 DNA/RNA Description: 7 exons. Protein Description: 442 residues. Expression: lung, placenta, kidney and skeletal muscle. Function: G protein-coupled receptor. Mutations WS4 is also caused by mutations in endothelin B receptor or in endothelin 3. How mutations in these genes lead to deafness and pigmentary abnormalities, shared by all the WS subtypes, was not elucidated. It was tempting to propose that the WS4 genes are directly or indirectly involved in the regulation of MITF expression that is crucial for melanocyte development. SLUG Location 8q11.21 DNA/RNA Description: 3 exons. Protein SLUG a zinc finger transcription factor is a marker of neural crest cells in Xenopus, zebrafish and chick embryos and probably has a functional role in formation of premigratory neural crest. In the mouse, the corresponding gene, Slugh, is expressed in migratory but not premigratory neural crest cells and is not essential for neural crest development. Description: 268 residues. Expression: Placenta, adult heart, pancreas, liver, kidney and skeletal muscle. Function: Transcriptional repressor. Atlas Genet Cytogenet Oncol Haematol. 2005; 9(2) To be noted Mouse models Mutant mice with coat color anomalies were helpful in identifying these genes, although the phenotypes of these mice did not necessarily perfectly match those of the four types of WS. There are several mice with mutations of murine homologs of WS genes and verify their suitability as models for WS with special interest in the cochlear disorder. The mice include splotch (Sp), microphthalmia (mi), Slugh -/-, WS4, JF1, lethalspotting (ls), and Dominant megacolon (Dom). 183 Waardenburg syndrome (WS) Vicente-Dueñas C et al. mouse model of WS2. These notions are consistent with the finding that WS2 is occasionally caused by mutations in EDNRB. lethal-spotted (ls) mice as a model for WS4 Homozygous mutations of the endothelin 3 (EDN3) gene cause coat spotting and aganglionic megacolon in ls mice and gene targeted edn3 null mice. Some of these mice can survive and mate; they are potentially a model for WS4, although cochlear disorders of these mice remain to be examined. Dominant megacolon (Dom) mice as a model for WS4 The Sox10 gene is mutated in the dominant megacolon (Dom) mouse, an animal model of neurocristopathy, whose phenotype is reminiscent of WaardenburgHirschsprung patients. The pigmentary phenotype also suggests that Sox10 expression is essential for melanocyte development. Homozygous Dom mice are lethal and their embryos lack neural crest-derived cells expressing the melanocyte lineage markers. Heterozygous Dom mice show white spotting and some of them show megacolon. Dom mice not respond to sound. They did not show endolymphatic collapse, suggesting that their stria vascularis had intermediate cells (melanocytes) sufficient for normal production of endolymph. However, their organ of Corti was missing. splotch (Sp) mice as a model for WS1 The mouse Pax3 gene was identified as the gene responsible for splotch (Sp) mice. Sp mice exhibit a number of characteristic developmental anomalies which predominantly affect the neural tube and neural crest. Severe alleles in six types of homozygous Sp mice are fatal at the embryonic stage, and even splotchretarded (Spd) mice, which have the least severe allele, encoding Pax3 with a substitution mutation at the paired domain, die at birth. Heterozygous Sp (Sp/+) mice survive after birth and have white belly spots, but curiously, showed no sign of auditory defects; WS1 patients are usually heterozygous at the PAX3 gene and yet many show auditory dysfunction. The phenotype of Spd mice varies depending on their genetic background, suggesting the existence of modifier genes. It has been estimated that at least two genes interact with Spd to influence the craniofacial features. microphthalmia (mi) mice as a model for WS2 Homozygous mi mice are microphthalmic due to the loss of retinal pigmentary epithelial (RPE) cells, white in coat color due to the loss of melanocytes, and deaf. 11 types of mi gene mutations, so far identified in mi mice, are transmitted in either a recesive or semidominant manner. In contrast, in humans is transmitted in a dominant manner. Slugh-/- mice as a model for WS2 Slugh-/- mice have diluted coat color, a white forehead blaze, and areas of depigmentation on the ventral body, tail and feet. Hearing function has not yet been assessed in Slugh-/- mice, but hyperactivity and circling behaviours observed in some Slugh-/- mice suggest a vestibule-cochlear disorder. WS4 mice as a model for WS4 Homozygous WS4 mice showed pigmentation anomaly (white coat color with black eye), aganglionic megacolon and cochlear disorder. Exons 2 and 3, which encode transmembrane domains III and IV of the Ednrb G-protein-coupled receptor protein, were deleted in these mice. Cochlea of WS4 mice showed endolymphatic collapse, due to the lack of melanocytes (intermediate cells) in the stria vascularis. JF1 mice as a model for WS2 The JF1 mice are an inbred strain of mice derived from Japanese wild mice, which are often bred by Japanese laymen as fancy „panda¾ mice because of their cute appearance with black eyes and white spotting on a black coat. JF1 mice are not lethal even in the homozygous state. This non-lethality of JF1 mice is probably due to the fact that the mutation in mice is an insertional mutation in intron 1 that creates a cryptic splicing acceptor site that results in decreased expression of wild-type Ednrb but does not cause aganglionic megacolon. As JF1 mice have pigmentation anomalies and hearing impairment- but not megacolon or dysmorphogenesis- they constitute a Atlas Genet Cytogenet Oncol Haematol. 2005; 9(2) References Southard-Smith EM, Angrist M, Ellison JS, Agarwala R, Baxevanis AD, Chakravarti A, Pavan WJ. The Sox10(Dom) mouse: modeling the genetic variation of Waardenburg-Shah (WS4) syndrome. Genome Res. 1999 Mar;9(3):215-25 Bondurand N, Pingault V, Goerich DE, Lemort N, Sock E, Le Caignec C, Wegner M, Goossens M. Interaction among SOX10, PAX3 and MITF, three genes altered in Waardenburg syndrome. Hum Mol Genet. 2000 Aug 12;9(13):1907-17 Tachibana M. MITF: a stream flowing for pigment cells. Pigment Cell Res. 2000 Aug;13(4):230-40 Touraine RL, Attié-Bitach T, Manceau E, Korsch E, Sarda P, Pingault V, Encha-Razavi F, Pelet A, Augé J, NivelonChevallier A, Holschneider AM, Munnes M, Doerfler W, Goossens M, Munnich A, Vekemans M, Lyonnet S. Neurological phenotype in Waardenburg syndrome type 4 correlates with novel SOX10 truncating mutations and expression in developing brain. Am J Hum Genet. 2000 May;66(5):1496-503 Verastegui C, Bille K, Ortonne JP, Ballotti R. Regulation of the microphthalmia-associated transcription factor gene by the Waardenburg syndrome type 4 gene, SOX10. J Biol Chem. 2000 Oct 6;275(40):30757-60 Konno P, Silm H. Waardenburg syndrome. J Eur Acad Dermatol Venereol. 2001 Jul;15(4):330-3 McCallion AS, Chakravarti A. EDNRB/EDN3 and Hirschsprung disease type II. Pigment Cell Res. 2001 Jun;14(3):161-9 Matsushima Y, Shinkai Y, Kobayashi Y, Sakamoto M, Kunieda T, Tachibana M. A mouse model of Waardenburg syndrome type 4 with a new spontaneous mutation of the endothelin-B receptor gene. Mamm Genome. 2002 Jan;13(1):30-5 184 Waardenburg syndrome (WS) Vicente-Dueñas C, et al. Sánchez-Martín M, Rodríguez-García A, Pérez-Losada J, Sagrera A, Read AP, Sánchez-García I. SLUG (SNAI2) deletions in patients with Waardenburg disease. Hum Mol Genet. 2002 Dec 1;11(25):3231-6 This article should be referenced as such: Vicente-Dueñas C, Bermejo-Rodríguez C, Pérez-Caro M, González-Herrero I, Sánchez-Martín M, Sánchez-García I. Waardenburg syndrome (WS). Atlas Genet Cytogenet Oncol Haematol. 2005; 9(2):181-185. Tachibana M, Kobayashi Y, Matsushima Y. Mouse models for four types of Waardenburg syndrome. Pigment Cell Res. 2003 Oct;16(5):448-54 Atlas Genet Cytogenet Oncol Haematol. 2005; 9(2) 185